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Employing a novel control function regression method that accounts for the endogenous matching of banks and executives, we find that equity portfolio vega, the sensitivity of executives’ equity portfolio value to their firms’ stock return volatility, leads to systemic risk that manifests during subsequent economic contractions but not expansions. We further find that vega encourages systemically risky policies, including maintaining lower common equity Tier 1 capital ratios, relying on more run-prone debt financing, and making more procyclical investments. Collectively, our evidence suggests that executives’ incentive-compensation contracts promote systemic risk-taking through banks’ lending, investing, and financing practices.

This paper examines how CEO inside debt holdings affect firms’ corporate social responsibility (CSR) activities. Using the US firm-level data over the 2006–2015 period, we find that firms with high CEO pensions and deferred compensation engage more in CSR. This positive relationship however is weakened for firms with greater CEO stock options. We further show that CEO inside debt holdings have a larger impact on CSR for firms in controversial industries where CSR is crucial for risk mitigation. Our results suggest that CEOs with higher inside debt holdings are less likely to take risks, thereby engaging in more CSR.

In addition to its well-documented alignment effect, managerial ownership can also have value-destroying effects by shifting risk to managers and encouraging risk-substitution; that is, managers with relatively unhedged personal portfolios tend to pass up profitable projects with high idiosyncratic (firm-specific) risk in favor of less-profitable projects that have greater aggregate (market) risk. Using parametric and semi-parametric estimation methods, we examine how managerial ownership influences firm value in light of the trade-off between the alignment and the risk-substitution effects. We find that risk-substitution offsets the alignment effect of managerial ownership in firms that are exposed to severe risk-substitution problems, leading to a weak (or non-existent) association between managerial ownership and firm value. We identify a plausible channel for these effects by showing that firms exposed to risk-substitution exhibit more “conservative” investment and financing policies. We also show that the risk-substitution problem is partially mitigated by the inclusion of stock options in managerial compensation packages. Finally, our findings suggest that semi-parametric methods may prove useful for future studies aiming at capturing nonlinear features in the data.

This paper contributes to our understanding of managers' motivations for initiating the sale of their company. Using a sample of 1098 publicly-listed US target firms with completed deals, we show that deals initiated by the target firm rather than by outside bidders have higher CEO ownership. Furthermore, CEOs are motivated to offer their firms for sale also by higher golden parachutes, stock and stock option grants prior to takeovers. Our results suggest that motivated CEOs participate actively in deal negotiations, rather than being bribed not to resist the deal. In target-initiated deal firms, CEO ownership and equity grants are also positively correlated with takeover premiums.\ud \ud \ud

Prior research in agency theory views outside directors as being mostly extrinsically motivated by the potential for financial rewards, and as such stresses the value of using director stock options and equity to incentivize outside directors to pursue strategic risks. We draw on and extend agency-theory by arguing that outside directors are primarily intrinsically motivated, and therefore excessive emphasis on pecuniary rewards and punishments can ironically subvert a director's motives away from strategic risk-taking. In particular, we claim that more important than extrinsic rewards and government regulations is creating a secure environment for directors so that they may exercise their fiduciary duties without fear of litigation. We test our theory on a sample of 196 S&P 500 firms from 2005 to 2015 and find that the pressures imposed on the board through external regulations and controls can often backfire and result in outside directors signing off on less risky expenditure. A strong implication of these findings is no real substitute exists to creating a safe environment for directors, where they have the freedom to pursue the long-term interests of the principals, even if this goes against the short-termism of capital markets.

We investigate the asymptotic behavior, as the number of options approaches zero, of the optimal exercise strategy of continuous-exercise perpetual executive stock options. Here the optimal strategy is described in terms of the free boundary of a degenerate variational inequality. To our knowledge, our method based on the convexity of the variational inequality at the initial time is new. Also, the unique formal asymptotic expansions of the free boundary and the solution of the variational inequality are derived.

In this paper, we present a valuation framework for pricing executive stock options that incorporates the vesting period, employment shocks as well as time-varying variances of the stock. A GARCH process is used to describe the variance of the stock and employment shocks are captured by a doubly stochastic Poisson process. Additionally, the proposed model allows for the correlation between the intensity and the variance of the stock. In the proposed framework, we derive a closed-form expression for executive stock options and investigate executive stock option prices numerically.

Although negative interest rates have been a phenomenon observed in capital markets for years, little research has been done on the impact of negative interest rates on stock option valuations. This paper shows that the fundamental assumption of equivalence between American and European call options at negative riskless interest rates is no longer universal. The findings are illustrated by means of an example. Furthermore, there are implications for practical trading with options.

We examine the information content of stock option implied volatility. We measure arrival intensities and magnitudes of various types of news, and find that these news measures are all positively associated with contemporaneous stock return volatility and many of them can be predicted by implied volatility. About 28% of the predictive power of implied volatility on future realized volatility is due to its ability to predict these news measures, and most of the predictive power is from predicting arrival intensities of both scheduled and unscheduled news. The predictive power is higher for fundamental news than for non-fundamental news.

Background: Israel recently initiated a rapid nationwide COVID-19 vaccination campaign to immunize persons ≥16 years of age and used exclusively Pfizer–BioNTech BNT162b2 mRNA COVID-19 vaccine according to schedule (two doses, 21 days apart). We provide the first estimates of the number of COVID-19 cases, hospitalizations, and deaths averted by a nationwide vaccination campaign. Methods: We used national surveillance data from the first 112 days (Dec 20, 2020 ‒ Apr 10, 2021) of Israel’s vaccination campaign to estimate averted burden of four outcomes: SARS-CoV-2 infections and COVID-19-related hospitalizations, severe or critical hospitalizations, and deaths. The direct effects of the immunization program were estimated for all susceptible individuals (i.e., no previous evidence of laboratory-confirmed SARS-CoV-2 infection) who were at least partially vaccinated (defined as receipt of at least one dose with ≥14 days after the first dose). Cases averted were estimated based on cumulative daily, age-specific rate differences comparing rates among unvaccinated to those who were at least partially vaccinated for each of the four outcomes and the (age-specific) size of the susceptible population and proportion that was at least partially vaccinated. Findings: Through Apr 10, 2021, we estimated that Israel’s vaccination campaign averted 158,665 (95% uncertainty range: 115,899‒201,431) SARS-CoV-2 infections, 24,597 (6,622‒42,571) hospitalizations, 17,432 (3,065‒31,799) severe and critical hospitalizations, and 5,533 (-1,146‒12,213) deaths. Of these, 66% of hospitalizations and 91% of deaths averted were among those ≥65 years of age. Seventy-three percent of SARS-CoV-2 infections and 79% of COVID-19-related hospitalizations and deaths averted stemmed from the protective effects in fully vaccinated persons. Interpretations: Without vaccination, Israel would have likely experienced triple the number of hospitalizations and deaths compared to what actually occurred during their largest wave of SARS-CoV-2 to date, which would have likely overwhelmed the healthcare system. Indirect effects and long-term benefits of the program, which could be substantial, were not included in these estimates and warrant future research. Funding: None. Declaration of Interest: John McLaughlin, Frederick Angulo, Farid Khan, Gabriel Mircus, Kaijie Pan, Jo Southern, David Swerdlow, and Luis Jodar hold stock and stock options in Pfizer Inc. Marc Lipsitch has provided advice on COVID-19 free of charge to Janssen, Astra-Zeneca, Pfizer, and COVAXX (United Biomedical), as well as to the nonprofit One Day Sooner and has received consulting income or honoraria from Merck, Bristol Meyers Squibb, and Sanofi, and institutional research support from Pfizer. All other authors report no conflicts.

We explore the role of female directors in mitigating CEO luck. CEOs are “lucky” when they receive stock option grants on days when the stock price is the lowest in the month of the grant, implying opportunistic timing. Our results show that board gender diversity significantly deters the opportunistic timing of option grants. The effect of board gender diversity is 17.19% stronger than that of board independence in reducing CEO luck. Board gender diversity plays an effective governance role, even more effective than board independence does. Our results support the benefits of board gender diversity in mitigating the agency cost.

Background: There are limited data on the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among pediatric-onset MS (POMS) patients and healthy controls. Using a prospective cohort of POMS patients and healthy controls, we aimed to determine the frequency of MOG-IgG and AQP4-IgG in both groups, compare clinical characteristics and outcomes in seronegative vs seropositive children, and identify predictors of final diagnosis. Methods: POMS patients and controls were enrolled at 14 US sites through a case-control study on POMS risk factors. Follow-up data were prospectively collected. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. Medical records were re-reviewed in seropositive cases to confirm final diagnosis. Findings: We included 1196 participants, 493 POMS and 703 controls. AQP4-IgG was negative in all participants. MOG-IgG was positive in 30/493 cases (6%) and 0/703 (0%) controls. Twenty-five of 30 MOG-IgG positives (83%) were determined to have MOG-IgG-associated disease (MOGAD) while 5/30 (17%) maintained a diagnosis of MS. The MOG-IgG false-positive rate was 1%. MOGAD cases, compared with MS, were more commonly female (84% vs 64%; p=0.044), presented at younger age (mean 8∙2±4∙2 vs 14∙7±2∙6 years; p

Unit 13 covers: • Compensating Owners and Execs in Unincorporated Entities • Compensating Owners and Execs in Corporations • Incentive Stock Options • Non-qualified Stock Options • Stock Appreciation Rights

Classic option pricing theory values a derivative contract via dynamic replication, and views the derivative as redundant relative to the replicating portfolio. In practice, while dynamic replication proves highly effective in drastically reducing the risk in derivative investments, the remaining risk can still be large and significant due to practical limits of arbitrage. Because of these limits, derivative securities can play primary roles in risk allocation and investors can demand compensation for taking these primary risks. This paper documents the effectiveness of delta hedging on U.S. stock options under practical situations, examines the cross-sectional and intertemporal variation of investment returns from writing options on different stocks, and attributes the return variation to variations in primary risk exposures in the delta-hedged option investments.

Background: On Dec 14, 2020, the United States initiated a nationwide COVID-19 vaccination campaign. Vaccination has not occurred uniformly in the United States. Only limited information describing the community-level impact of national vaccination campaigns is available. Methods: Using a negative binomial regression model we evaluated the association between county-level COVID-19 vaccine uptake and rates of COVID-19 cases and deaths in the United States from April 1, 2021 through July 31, 2021 controlling for a broad set of county-level environmental, sociodemographic, economic, and health-status-related characteristics. Findings: After adjustment for county-level characteristics, US counties with ≥70% of their adult population fully vaccinated against COVID-19 had 32% (95% CI: 19-43; P =

Background: The current COVID-19 pandemic has raised a major challenge to healthcare systems Deployment of telehealth solutions can help maintaining continuity of care while limiting pts' and healthcare workers’ exposure with the virus In this context, Gustave Roussy Cancer Institute has implemented a pts reported outcome platform (CAPRI-COVID) to improve monitoring and effective management of COVID-19 positive pts with cancer Methods: CAPRI-COVID consists in a mobile application (CAPRI App) and a telephone platform with a dedicated call number, the entire procedure being managed by four NNs After an initial assessment by the NNs, remote monitoring of 6 COVID-related symptoms were collected daily, either by the patient via the CAPRI App or by NNs during a phone call In case of worsening or emerging symptoms, an automated alert was sent to the platform;NN assessed the clinical condition and could ask for a medical advice if necessary The monitoring period was 14 days (with at least 2 days with complete regression of symptoms) Each intervention performed by NNs was tracked on the platform, as well as pts-reported data This analysis presents the data collected via the platform from March 23 to May 4 2020 Results: Overall, 116 COVID-positive pts have completed the monitoring period (median age: 58 5 years, 21-90;56 9% female) 54 3% were monitored after hospitalization for COVID-19, 37 1% after RT-PCR screening (symptomatic pts) and 8 6% for systematic screening prior to surgery There were no deaths or admissions to intensive care unit 7 8% of pts were hospitalized (excluding scheduled hospitalization) NNs conducted an average of 9 9 calls per patient Of 53 events requiring a medical opinion, 50 9% resulted in a visit to the emergency room 41 4% of pts downloaded the CAPRI App, and completed the tracking data on average 1 1 times per day Conclusions: CAPRI-COVID enabled to keep the majority of pts at home, and helped to ensure secure pts’ pathways during this epidemic NNs play an essential role in addition with the use of CAPRI App which helped limiting phone calls and focusing on the management of complex pts Ongoing analyses are exploring actions of NNs and pts’ experience Legal entity responsible for the study: Gustave Roussy Funding: Has not received any funding Disclosure: O Mir: Honoraria (self), Travel/Accommodation/Expenses: Amgen;Honoraria (self), Honoraria (institution): AstraZeneca;Honoraria (self), Research grant/Funding (institution): Bayer;Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines;Honoraria (self): Bristol-Myers Squibb;Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly;Honoraria (self), Honoraria (institution), Advisory/Consultancy, Shareholder/Stockholder/Stock options: Ipsen;Honoraria (self): Lundbeck;Honoraria (self): MSD;Honoraria (self), Honoraria (institution): Novartis;Honoraria (self), Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer;Honoraria (self), Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche;Honoraria (self), Speaker Bureau/Expert testimony: Servier;Honoraria (self): Vifor Pharma;Shareholder/Stockholder/Stock options: Amplitude Surgical;Honoraria (self), Shareholder/Stockholder/Stock options: Transgene;Honoraria (institution): PharmaMar F Scotte: Honoraria (self): CIO Roche;Honoraria (self): MSD;Honoraria (self): Pierre fabre Oncology;Honoraria (self): Leo Pharma;Honoraria (self): BMS;Honoraria (self): Pfizer;Honoraria (self): Mundi Pharma;Honoraria (self): Mylan All other authors have declared no conflicts of interest

Using FAS 123R as an exogenous shock to stock options, I provide evidence that equity‐based risk‐taking incentives discourage corporate social responsibility (CSR). This finding suggests that compensation incentives can motivate managers not to pursue CSR strategies because CSR reduces firms’ risk and provides insurance‐like benefits. Firms with a greater demand for CSR's risk reduction are more sensitive to changes in risk‐taking incentives. I triangulate my results by confirming that CSR weaknesses are positively related to subsequent stock return volatility. Overall, using a robust empirical design, I find that risk‐taking incentives are a determinant of firms’ CSR.

Prior research establishes that boards of directors can encourage risk-averse managers to take risky actions by providing stock options and severance pay. We demonstrate that the ability of these incentives to encourage risk-taking hinges on the level of uncertainty facing the manager, and that the level of uncertainty varies across time. We confirm prior findings that stock option convexity encourages risk-taking, but find that this relation only holds when the level of uncertainty is low. We also confirm prior findings that severance pay encourages risk-taking, but find that this relation only holds when the level of uncertainty is high. Finally, we find that compensation committees respond to uncertainty by adjusting the level of option compensation. Overall, our results suggest that the effectiveness of incentives to take risk varies with the level of uncertainty facing the manager, and that boards consider this in annual compensation design.

This paper provides evidence that the availability of individual stock options adds value to security issuers. We focus on convertible bond issues because pricing convertible bonds requires essentially the same set of information necessary to price options. By exploiting the SEC’s minimum stock price requirement for option listing to employ a regression discontinuity design, we find that the availability of stock options significantly affects the pricing of convertible bonds. In line with options providing information, the effect is stronger when the overall information environment is poor. Listed options help issuers attract more convertible bond buyers and reduce the cost of financing. Overall, our results highlight the value relevance of the options market.

This paper investigates the impact of employee stock options (ESO) on labor unions’ likelihood to initiate strikes. Using the unique setting of union elections in U.S. firms, we find that firms offering higher levels of equity incentives to their employees are exposed to significantly lower post-unionization strike risk. Furthermore, firms strategically grant more stock option incentives to employees in response to the unionization of the labor force. The increase in option incentives is more pronounced among firms holding union elections in states with stronger union bargaining power and when the strike risk is perceived to be higher.

This study examines the relationships between excess corporate cash holding and equity option market liquidity over the period from Jan 3, 2005 to Dec 31, 2019. We show that the level of cash reserve in excess of what can be captured by firm characteristics significantly explains the liquidity of stock options. Trading volume and open interests of the options increase in companies with a higher magnitude of excess cash while the bid-ask spreads of stock options decline in excess cash. Our findings confirm the theoretical predictions by Gopalan et al. (2012) that excess cash improves market liquidity as it reduces adverse selection problems caused by the uncertainty in firm valuations. This relation remains more pronounced with put options, out-of-the money contracts or those with short maturities. In addition, excess cash has stronger impacts on option liquidity within firms with a greater degree of informed trading or during periods of high volatility in financial markets. Our result shows that when the uncertainty about prospects of firms rises, excess cash becomes more valuable and affects option market liquidity.

We examine the effect of financial markets on the tone manipulation of earnings press releases by CEOs. We find that CEOs with high compensation convexity are significantly more likely to employ positive tone management right after recent high industry returns. Further analysis shows that this opportunistic behavior is concentrated in firms with weak corporate governance. The positive tone management has a positive stock return effect around the earnings announcement and significantly increases subsequent idiosyncratic return volatility. CEOs benefit from the tone management by exercising stock options and selling stocks around earnings announcements. Our results suggest that managers may extract information from capital markets to learn the optimal timing to engage opportunistic behavior.

The illiquidity risk premium hypothesis implies the existence of a positive relation between illiquidity in the option market and option returns. Based on numerous studies within the extant literature examining the roles of informed traders in the option markets, we explore how information asymmetry and short sales affect the illiquidity risk premium hypothesis. We find that the illiquidity risk premium is higher for both call and put options of those firms with higher information asymmetry, which is particularly driven by small firms. We also find that it is higher for put (call) options of those stocks with lower (higher) short-sale supply (demand).

We show evidence of a liquidity searching behaviour of informed investors in option listings, which was also found by Collin-Dufresne and Fos (2015) using stock markets. Nevertheless, and differently from Collin-Dufresne and Fos (2015), we find that the option bid–ask spread may be still a good proxy for informed trading, despite of the liquidity searching behaviour of informed agents. We show an upward trend in the option bid–ask spread after option introductions (as informed traders avoid trading in initial periods after listing dates due to the low liquidity environment), which is steeper for options with high chances of information asymmetries.

We utilize a Benford distribution to examine the earnings management change following the Korean financial reforms. We examine the propensity of Korean firms to convert high second-from-the-left and third-from-the-left digits of their net income in the post-financial reform period (2000–2012) compared to the pre-financial reform period (1990–1996). We show that managers convert high second (third) digits of positive net income to improve first (second) digits, but try to retain high second digits of negative net income to avoid an increase in first digits. However, these results are stronger in the post-financial reform period than in the pre-financial reform period. This is possibly due to an increase in performance-based evaluation and market-oriented systems following the financial reforms. Additional analyses indicate that the existence of stock options was a driver of this increase in earnings management.

This paper develops a model for the valuation of executive stock options (ESOs) considering two sources of early exercise: forced exercise due to executive turnover and voluntary exercise due to personal considerations. Using data of about 4000 US executives, I estimate separate hazard rate factor models for both sources of early exercise. In a second step, I combine both conditional hazard exercise models for the valuation of a representative ESO in a Monte Carlo simulation. Analysis of the individual valuation impact of each source of early exercise shows that turnover induced exercises are responsible for most of the valuation discount of ESOs to market traded options. This result is important as most of the current literature on ESOs concentrates solely on voluntary exercises. I further find that the common practice valuation approach suggested by the Financial Accounting Standards Board (FASB) consistently underestimates ESO values.

This paper provides an empirical explanation of the more frequent use of restricted stock plans for executives than stock option plans, to reveal the determinants of a restricted stock plan and understand its subsequent effects. We find that firms with higher growth opportunity, smaller size, higher executive ownership, smaller rent-seeking probably, and dividend payment prefer to grant restricted stock plans. Moreover, the preference of regulators drives the tendency of using restricted stock plans, designed to have higher pay-performance sensitivity (delta) and lower pay-risk sensitivity (vega). Under the intensive regulation, the restricted stock plans designed by firms with executive ownerships and large agency debt costs are more sensitive to risk. As a result, granting restricted stock plans rather than stock options helps improve firm performance and the preference of regulators on restricted stock plans can also enhance firm performance and decrease firm risks.

This paper investigates the impact of bank executive pay limits on discretionary loan loss provisions (DLLPs) in the context of a large emerging economy, such as that of China. We find that a bank executive pay limit primarily aimed at temporarily suspending stock option incentive plans leads to a significant rise in income-decreasing DLLPs, whereas a pay limit implemented to restrict the total emoluments leads to a significant decline in income-increasing DLLPs. Moreover, the degree of the impact of pay limits on bank DLLPs varies with CEOs’ personal characteristics and bank executive perquisites.

PURPOSE/OBJECTIVE(S) Most Gamma Knife stereotactic radiosurgery (GKRS) procedures have been performed using water-based dose calculation algorithms with magnetic resonance imaging (MRI) only. We present a dose calculation method that can take into account the inhomogeneity effect in routine GKRS treatment planning without CT imaging for every patient. MATERIALS/METHODS Twenty-five patients who underwent GKRS at our institution with T1- and T2-weighted whole head MRI as well as brain CT images were selected for this study. Two set of synthetic computed tomographies (sCT) were generated from T1 and T2 MRI using cycle consistent generative adversial networks architecture (cGAN). Images from 20 patients were used to train the algorithm. The other 5 sets of data were used for testing and validation. The sCT images generated were evaluated in terms of the preservation of anatomical structures, the Hounsfield unit accuracy and the overall image quality. All sCT images from the 5 test patients were imported into GammaPlan version 11.1 for dosimetric analyses. We performed dose calculations for each test patient using the water-based TMR algorithm and the convolution algorithm with electron densities from the original CT, the T1-based sCT and the T2-based sCT. RESULTS The main features of the original CT images (skull shape, bone & air inhomogeneity etc.) for the 5 test patients were successfully reproduced in the sCT images. sCT images from the T1-weighted MRI are in general closer to the original CT images compared to the T2-weighted MR images. For the same dose prescription and same shot arrangement, the maximum difference between the treatment shot times from the CT-based convolution calculation and the TMR calculation is 10.2%. The maximum differences between the treatment shot times from the CT-based convolution calculation and the convolution calculations from the sCTs from the T1 and T2 MR images are 2.3% and 3.8%, respectively. CONCLUSION sCT images from brain MRI can be used for the inhomogeneity correction in GKRS dose calculation. T1-weighted MRI may work better than T2-weighted MRI for this purpose. AUTHOR DISCLOSURE F. Li: None. Y. Xu: None. O.D. Lemus: None. T.J. Wang: Research Grant; AbbVie, Merck, RTOG Foundation, Genentech. Honoraria; Elekta, Wolters Kluwer, Cancer Panels, Rutgers, University of Iowa. Consultant; Doximity, Elekta. Advisory Board; Novocure, AstraZeneca. Travel Expenses; AbbVie, Elekta, Novocure. Stock Options; Doximity. M.B. Sisti: None. C. Wuu: None.

This study adopts a new perspective, misvaluation, to explain corporate propensity to hold cash. We find a strong cross-sectional relationship between misvaluation and the propensity to hold cash, which can be attributed to firms’ equity-raising activities and the exercise of employee stock options. The results are robust after controlling for endogeneity issues. Several additional robustness tests reject alternative explanations, such as precautionary motives, agency conflicts, near-term cash needs, and tax motives. Additionally, the study examines the value of cash and shows that misvaluation can increase the value of cash held by firms that are financially constrained or have greater growth opportunities.

The paper examines the extent and potential reasons for non-exercise of ‘in the money’ stock options, drawing on employee-level data from the UK Save-As-You-Earn stock option plan. 14 per cent of participants choose not to exercise, and failure to exercise in these circumstances can be costly in terms of foregone increases in wealth. Lesser experience of the option plan, perceived lack of financial knowledge, and greater reliance on friends for advice is associated with failure to exercise. These findings offer challenges to the use of sophisticated reward and benefit schemes by companies when potential participants lack financial capabilities, and add to the literature by showing that financial literacy can remain problematic even when employees have surmounted initial obstacles to joining plans.

We investigate the importance of ambiguity, or Knightian uncertainty, in executives' decisions about when to exercise stock options. We develop an empirical estimate of ambiguity and include it in regression models alongside the more traditional measure of risk, equity volatility. We show that each variable has a statistically significant effect on the timing of option exercises, with volatility causing executives to hold their options longer in order to preserve remaining option value, and ambiguity increasing the tendency for executives to exercise early in response to risk aversion. Regression estimates for the volatility and ambiguity variables imply similar magnitudes of economic impact upon the exercise decision, with the volatility variable being about 2.5 times stronger.

We examine unexplored factors that affect the ex-post adoption rates of newly listed stock options. We show that a variety of measures of information asymmetries concerning underlying stocks predict option adoption rates. These predictive relationships are robust after including factors that have been found to be significant in earlier literature, such as stock volatility and volume. Moreover, we report that not only do information asymmetries prior to option listings forecast a successful listing, but also that successful listings themselves end up reducing ex-post the extent of the information asymmetries affecting a stock.

© 2016 Elsevier B.V. Call, Kedia and Rajgopal (2016) provide intriguing evidence concerning the apparent role of employee stock options in inducing rank and file employees to be complicit in corporate misconduct. They conclude that granting options to rank and file employees provides incentives for them to facilitate misreporting and discourages them from whistleblowing. In this discussion, I argue that the evidence is largely circumstantial and puzzling in several respects. I conclude that while Call et al. have identified intriguing evidence, further research is required to rule out alternative explanations and to better understand employees’ motives.

We find that firms grant more rank and file stock options when involved in financial reporting violations, consistent with managements’ incentives to discourage employee whistle-blowing. Violating firms grant more rank and file options during periods of misreporting relative to control firms and to their own option grants in non-violation years. Moreover, misreporting firms that grant more rank and file options during violation years are more likely to avoid whistle-blowing allegations. Although the Dodd-Frank Act (2010) offers financial rewards to encourage whistle-blowing, our findings suggest that firms discourage whistle-blowing by giving employees incentives to remain quiet about financial irregularities.

We investigate the relation between the option returns and the underlying stock's lottery-like characteristics. Call options written on the most lottery-like stocks underperform otherwise similar call options written on the least lottery-like stocks by 10–20% per month. Moreover, the more lottery-like the underlying stocks, the further and more frequently the options deviate from the put–call parity in the direction induced by overvalued calls. Furthermore, the lottery-like characteristic effect is stronger during periods of high investor sentiment. The results suggest that optimism-induced gambling preference causes lottery-like options to be overvalued.

Background Somatic KRAS mutations are detected in approximately 15%-30% of lung adenocarcinomas, with regional variation, and are associated with poor prognosis. We explored the prevalence of KRAS mutations and their association with efficacy in participants (pts) with non-squamous NSCLC enrolled in the KEYNOTE-042 study of pembrolizumab monotherapy vs platinum-based chemotherapy as first-line therapy for advanced PD-L1-positive (TPS ≥1%) NSCLC (NCT02220894). Methods KRAS mutational status and tumor mutational burden (TMB) were assessed by whole-exome sequencing (WES) in pts with who had available tumor and matched-normal tissue. This exploratory analysis included descriptive analyses of the correlation between KRAS mutational status and shifts in distributions of TMB and PD-L1 expression and the association of KRAS and KRAS G12C status with efficacy. Results Of the 782 pts with non-squamous histology, 301 (38%) were evaluable by WES and had matched tumor and normal DNA. KRAS mutations were identified in 69 (23%) pts, including 29 (10%) G12C carriers. Pts with vs without KRAS mutation tended to have higher PD-L1 TPS (median [IQR] 60% [10-95] vs 35% [10-80]) and TMB (median [IQR] 191 [129-288] vs 105 [56-226] mut/exome). Outcomes of pembrolizumab and of chemotherapy for pts with and without KRAS mutation and for KRAS G12C carriers are in the table. Of note, CIs were wide given the modest frequency of KRAS mutation and low frequency of KRAS G12C.TableLBA4TableWith Any KRAS MutationWith KRAS G12C MutationWithout Any KRAS MutationPembro Mono-therapy (N = 30)Chemo-therapy (N = 39)Pembro Mono-therapy (N = 12)Chemo-therapy (N = 17)Pembro Mono-therapy (N = 127)Chemo-therapy (N = 105)ORR, % (95% CI)56.7 (37.4-74.5)18.0 (7.5-33.5)66.7 (34.9-90.1)23.5 (6.8-49.9)29.1 (21.4-37.9)21.0 (13.6-30.0)PFS, median, mo (95% CI)12 (8-NR)6 (4-9)15 (10-NR)6 (4-8)6 (4-7)6 (6-8)PFS, HR (95% CI)0.51 (0.29-0.87)0.27 (0.10-0.71)1.00 (0.75-1.34)OS, median, mo (95% CI)28 (23-NR)11 (7-25)NR (23-NR)8 (5-NR)15 (12-24)12 (11-18)OS, HR (95% CI)0.42 (0.22-0.81)0.28 (0.09-0.86)0.86 (0.63-1.18) Conclusion Findings of this descriptive exploratory analysis suggest that pembrolizumab monotherapy should be considered as a standard first-line treatment option for PD-L1-positive advanced non-squamous NSCLC regardless of KRAS mutational status. These findings also suggest that a pembrolizumab-containing regimen is a clinically relevant comparator for studies of KRAS -targeted therapy given as first-line treatment of NSCLC. Clinical trial identification KEYNOTE-042; NCT02220894. Editorial acknowledgement Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, for writing support. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure R.S. Herbst: Advisory / Consultancy: Abbvie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Infinity Pharmaceuticals; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (self): Merck & Co., Inc., Kenilworth, NJ, USA; Advisory / Consultancy: Nektar; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: NextCure; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Shire PLC; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Tocagen; Officer / Board of Directors: Junshi Pharmaceuticals. G. Lopes: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Merck & Co., Inc.. D.M. Kowalski: Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS. K. Kasahara: Research grant / Funding (institution): MSD. Y-L. Wu: Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi. G. De Castro Jr.: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer-Ingelheim; Honoraria (self), Honoraria (institution): Novartis; Honoraria (institution): Amgen; Honoraria (institution): Astellas. B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Bristol Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Yuhan. H.Z. Turna: Research grant / Funding (institution): MSD. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Pietanza: Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: Merck Sharp & Dohme. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Leadership role, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): SFJ Pharmaceuticals; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Xcovery; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options: Hutchinson MedPharma; Honoraria (self): Janssen; Honoraria (self): Takeda; Honoraria (self): Fishawack Facilitate Ltd; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: ACEA Biosciences Inc.; Advisory / Consultancy: Celgene, Vertex, geneDecode, OncoGenex, Ignyta; Leadership role, Shareholder / Stockholder / Stock options: Sanomics Ltd; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Cirina; Non-remunerated activity/ies, ASCO board of directors: ASCO; Non-remunerated activity/ies, track chair for ESMO 2019: ESMO.

Background An ongoing open-label, multiarm, multicenter, phase I study of the anti–CTLA-4 antibody MK-1308 in combination with pembrolizumab in advanced solid tumors (NCT03179436) revealed manageable safety and promising efficacy in patients (pts) with advanced non-small cell lung cancer receiving first-line therapy [Perets et al. J Clin Oncol. 2019;37(suppl):2558]. Here we report data from the small cell lung cancer (SCLC) cohort of this study. Methods In the dose confirmation phase, pts with advanced SCLC received MK-1308 at 75 mg Q6W + pembrolizumab 200 mg Q3W (up to 35 cycles). The primary end point was safety, and the secondary end point was ORR based on blinded independent central review (BICR) per RECIST v1.1. PFS based on BICR per RECIST v1.1 and OS were exploratory end points. The database cutoff date for this analysis was June 3, 2019. Results Forty pts with previously treated advanced SCLC (second-line or beyond) were enrolled and dosed; median duration of follow-up was 11 mo. At data cutoff, 32 pts (80%) discontinued study treatment—23 (58%) due to progressive disease, 4 (10%) due to AE, 2 (5.0%) due to clinical progression—and 3 (7.5%) withdrew consent. Median age was 66 years; 60% of pts were male and 65% had ECOG PS 1 at baseline. Seven pts achieved partial response according to BICR assessment, for an ORR of 18% (95% CI, 7.3-33). Eight pts (20%) had a best overall response of stable disease and 21 (53%) had progressive disease. Response duration ranged from 2.9 to 8.4+ mo. At the time of the data cutoff, 5 of 7 responses (71%) were ongoing. Median time to response was 2.1 mo (range, 1.1-12). Median PFS was 2.0 mo (95% CI, 1.9-3.9), and the 6-mo PFS rate was 26%. Median OS was 11 mo (95% CI, 5.9-not reached), and the 6-mo OS rate was 66%. Treatment-related adverse events (TRAEs) as determined by the investigator occurred in 32 pts (80%). Grade 3 TRAEs were reported in 11 pts (28%); no grade 4-5 events were reported. Three pts (7.5%) discontinued treatment due to TRAEs. Conclusion In heavily pretreated pts with SCLC, MK-1308 + pembrolizumab was generally well tolerated with encouraging antitumor activity. Clinical trial identification NCT03179436. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics; Shareholder / Stockholder / Stock options: Gencurix Inc. K. Yoh: Research grant / Funding (institution): MSD. J. Bar: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: OncoHost; Advisory / Consultancy: VBL; Research grant / Funding (institution): Pfizer. A. Nagrial: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Incyte. D.R. Spigel: Leadership role: Centennial Medical Center; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Genentech; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. M. Gutierrez: Shareholder / Stockholder / Stock options: COTA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Esanex; Advisory / Consultancy: Guardant 360; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Foundation Medicine. D-W. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. D. Rasco: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron. M. Satouchi: Honoraria (self), Research grant / Funding (institution): MSD. M-J. Ahn: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy: Alpha Pharm. D.H. Lee: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): ChongKunDang; Honoraria (self): CJ Healthcare; Honoraria (self): Eli Lilly; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Samyang Biopharm; Honoraria (self), Advisory / Consultancy: ST Cube; Honoraria (self): Takeda. C. Maurice-Dror: Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche. S. Siddiqi: Full / Part-time employment: Merck & Co., Inc.. X. Li: Full / Part-time employment: Merck & Co., Inc.. J. Cyrus: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R.A. Altura: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R. Perets: Advisory / Consultancy: Karyopharm; Advisory / Consultancy: BiolineRx. All other authors have declared no conflicts of interest.

Background Corticosteroids (CS) are often prescribed for patients (pts) with cancer to alleviate disease symptoms, manage treatment-related adverse events, or treat underlying comorbidities. Immunosuppressive properties of CS may impact the effectiveness of cancer immunotherapy (CIT) if given concomitantly. This study explored the association of baseline CS use with outcomes in CIT-treated pts with advanced melanoma (aMel), advanced non-small cell lung cancer (aNSCLC) or advanced urothelial cancer (aUC). Methods Retrospective observational study of pts in the Flatiron Health de-identified electronic health record–derived database diagnosed Jan 2011-Jun 2017 with aMel, aNSCLC or aUC and treated with CIT only in any line. Baseline CS use was defined as intravenous or intramuscular administration or oral orders ≤14 days prior and up to 30 days after start of CIT. Association of baseline CS use with overall survival (OS) was estimated using multivariable Cox proportional hazards models adjusted for key baseline characteristics. Results Most pts were white males aged 66-72 years at first CIT treatment. Most pts with aNSCLC (56%) or aUC (59%) received 2L CIT; patients with aMel (89%) used CIT in 1L. Pts taking baseline CS (19%-30%) were more likely to have stage IV disease at diagnosis, brain metastases, liver metastases (aNSCLC, aUC) and poorer ECOG PS scores (aUC) at baseline. The use of baseline CS was associated with a 23%-47% higher risk of death compared with no use in multivariable models.Table47O Patient characteristics by BL CS use, OS by CS useTableaNSCLC (n = 862)aMel (n = 742)aUC (n = 609)CS (n = 258)No CS (n = 604)CS (n = 182)No CS (n = 560)CS (n = 116)No CS (n = 493)Age at CIT start, mean (SD), years68.2 (9.6)68.5 (9.8)66.1 (13.0)66.9 (13.0)73.0 (8.9)72.6 (8.9)Female484528312726Non-Hispanic white717085856875CCI Conclusion Baseline CS was associated with shorter survival for pts treated with CIT and not explained by measured confounders. These results suggest that avoidance of CS should be considered at the initiation of treatment, when possible and appropriate, to maximize the potential benefits of CIT. Further studies are needed to confirm these observations. Editorial acknowledgement Medical writing assistance for this abstract was provided by Jeff Frimpter, PhD, of Health Interactions, Inc., and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the study F. Hoffmann-La Roche, Ltd. Funding F. Hoffmann-La Roche, Ltd. Disclosure A. Drakaki: Advisory / Consultancy, Travel / Accommodation / Expenses: AZ; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Radmetrix; Research grant / Funding (institution): Kite Pharma; Travel / Accommodation / Expenses: ElI Lilly; Shareholder / Stockholder / Stock options: Urogen; Shareholder / Stockholder / Stock options: Allogene; Shareholder / Stockholder / Stock options: Kynan Pharma; Full / Part-time employment: Ucla. P. Luhn: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. H. Wakelee: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, ad board participation (compensated): AZ; Advisory / Consultancy, Research grant / Funding (institution), ad board participation (compensated): Xcovery; Advisory / Consultancy, ad board participation (compensated): Janssen; Advisory / Consultancy, ad board participation (compensated): Mirati; Advisory / Consultancy, ad board participation (compensated): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution), Advisory board (not compensated): Merck; Advisory / Consultancy, Advisory board (not compensated): Takeda; Advisory / Consultancy, Research grant / Funding (institution), Advisory board (not compensated): Genentech/Roche; Advisory / Consultancy, Advisory board (not compensated): Cellworks; Research grant / Funding (institution): ACEA Biosciences; Research grant / Funding (institution): Arrys Therapeutics; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Cellgene; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Gilead; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Pfizer. P.K. Dhillon: Full / Part-time employment: Genentech. J. Shim: Full / Part-time employment: Roche. V. Degaonkar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech/Roche. T. Hoang: Full / Part-time employment: Genentech. V. McNally: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. S.Y. Chui: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech/Roche. R. Gutzmer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Almirall-Hermal; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck-Serono; Honoraria (self): AZ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: SUN; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre-Fabre; Advisory / Consultancy: 4SC; Advisory / Consultancy: Incyte; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Johnson & Johnson. All other authors have declared no conflicts of interest.

Background Immunotherapy with or without chemo has improved survival vs chemo in 1L aNSCLC. NIVO + chemo showed encouraging activity in a phase 1 study in this setting. CheckMate 227 is a multi-part, randomized, open-label, phase 3 study evaluating NIVO-based regimens vs chemo. We present final results from Part 2, which evaluated NIVO + chemo vs chemo in 1L aNSCLC. Methods Pts (N = 755) with chemo-naive, stage IV or recurrent NSCLC, ECOG PS 0–1, and no sensitizing EGFR/ALK alterations were randomized 1:1 to receive every 3 weeks NIVO 360 mg + chemo or chemo. Pts were stratified by histology (squamous [SQ] vs non-squamous [NSQ]), sex, and PD-L1 expression ( Results Baseline characteristics were generally balanced. Minimum follow-up was 19.5 mo. In pts with NSQ NSCLC, no statistically significant improvement in OS was seen with NIVO + chemo vs chemo (HR, 0.86 [95.62% CI, 0.69–1.08; P=0.1859]); median OS was 18.8 mo vs 15.6 mo; 12-mo OS rates were 67.3% vs 59.2%. HR for OS was 0.81 (95% CI, 0.67–0.97) in all randomized pts; 0.69 (95% CI, 0.50–0.97) in pts with SQ NSCLC. Progression-free survival and objective response rates favored NIVO + chemo in NSQ, SQ, and all randomized pts (table). Grade 3–4 tx-related adverse events occurred in 45% and 35% of all pts treated with NIVO + chemo and chemo, respectively.TableLBA3 Efficacy outcomes with 1L NIVO + chemo vs chemo in pts with NSQ NSCLC, SQ NSCLC, and in all randomized ptsTableNSQ NSCLCSQ NSCLCAll Randomized PtsNIVO + chemoChemoNIVO + chemoChemoNIVO + chemoChemon=270n = 273n=107n = 105n=377n = 378OSEvents, n (%)156 (57.8)164 (60.1)68 (63.6)75 (71.4)224 (59.4)239 (63.2)Median, mo18.815.618.312.018.314.7HR (95% CI)0.86 (0.69–1.08)aP = 0.18590.69 (0.50–0.97)0.81 (0.67–0.97)12-mo OS rate, %67.359.266.148.566.956.2PFSEvents, n (%)187 (69.3)200 (73.3)79 (73.8)82 (78.1)266 (70.6)282 (74.6)Median, mo8.75.87.14.48.45.5HR (95% CI)0.67 (0.55–0.82)0.51 (0.37–0.70)0.62 (0.52–0.73)12-mo PFS rate, %39.525.731.79.337.321.3Objective response rate, n (%)130 (48.1)80 (29.3)64 (59.8)34 (32.4)194 (51.5)114 (30.2)a95.62% CI Conclusion CheckMate 227 Part 2 did not meet the primary endpoint of OS for NIVO + chemo vs chemo in NSQ NSCLC. Descriptive analyses showed longer OS with NIVO + chemo in all randomized pts and SQ NSCLC. No new safety signals were observed. Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure L. Paz-Ares: Honoraria (self): Roche, MSD, Lilly, Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Sanofi, Pharmamar, Pfizer, Bristol-Myers Squibb, Merck, Takeda, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint; Leadership role: Altum Sequencing; Research grant / Funding (institution): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb; Officer / Board of Directors: Genomica. T.E. Ciuleanu: Advisory / Consultancy: Astellas, Janssen, Bristol-Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Lilly, AstraZeneca, MSD, Sanofi, Novartis, Servier, AD Pharma. A. Pluzanski: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche, Takeda; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche. A. Nagrial: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; Research grant / Funding (institution): Astra Zeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche. R. Kowalyszyn: Advisory / Consultancy: Astellas, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, MSD, Novartis; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche. C. Audigier-Valette: Honoraria (self): AbbVie, Pfizer; Honoraria (institution): Roche, MSD, Bristol-Myers Squibb, AstraZeneca; Advisory / Consultancy: Roche, MSD, Bristol-Myers Squibb, AstraZeneca, AbbVie, Pfizer. Y-L. Wu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, BMS, Roche; Non-remunerated activity/ies: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche. H. Borghaei: Honoraria (self): University of Pennsylvania, CAR T Program, Takeda [Data and Safety Monitoring Board]; Advisory / Consultancy: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, GLG; Research grant / Funding (self): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly. M.D. Hellmann: Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, Syndax, Shattuck Labs, Immunai, Nektar, Blueprint Medicines; Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb, AstraZeneca; Shareholder / Stockholder / Stock options: Shattuck Labs, Immunai. J. Brahmer: Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Amgen. M. Reck: Honoraria (self): AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Ramalingam: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Loxo, Tesaro, Merck, Daichi; Advisory / Consultancy: Amgen, AbbVie, Lilly, Genentech, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Amgen, AstraZeneca, Takeda, Advaxis, Tesaro, Merck. L. Zhang: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, MSD, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Pfizer, Henrui Pharm. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. K.J. O'Byrne: Advisory / Consultancy: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Novartis, Teva, Janssen-Cilag, Natera; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Janssen-Cilag, Mundipharma; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Shareholder / Stockholder / Stock options: Carp Pharmaceuticals, Carpe Vitae Phaemaceuticals; Licensing / Royalties: Various patents issues with licensee as listed. Queensland University of Technology and Trinity College Dublin. All other authors have declared no conflicts of interest.

Background Checkpoint Inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (mNSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for pts with poor prognostic features or negative predictive clinical factors for CPI benefit, including PD-L1 negative (-) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor. BEMPEG + CPI has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in pts with multiple solid tumors (Diab A, ASCO 2018; Siefker-Radtke A, ASCO-GU 2019). Given the early efficacy data and favorable safety profile of BEMPEG + nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Trial Design This phase I/II multinational trial evaluates BEMPEG + PEMBRO in pts with locally advanced or metastatic solid tumors. There are two key components to the study: 1) Dose optimization: which includes 3 + 3 and step-up dosing (U.S. enrollment only) and will include ∼40 pts with first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma, regardless of PD-L1 status; 2) Dose expansion: which includes ∼58 first-line mNSCLC pts (enrolling globally). The expansion cohort will evaluate the preliminary anti-tumor activity of BEMPEG, in combination with PEMBRO, in first-line mNSCLC, regardless of PD-L1 status ( 50%). The primary objectives in the dose optimization cohorts are safety and tolerability of the combination and to determine the maximum tolerated dose, recommended phase II dose and optimal dosing schedule of BEMPEG in combination with PEMBRO in locally advanced or metastatic solid tumors. The primary objective in the dose expansion cohort is objective response rate by RECIST 1.1. Enrollment is ongoing. Clinical trial identification NCT03138889. Legal entity responsible for the study Nektar Therapeutics. Funding Nektar Therapeutics. Disclosure M. Reck: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene. F. Cappuzzo: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Lilly. D. Rodriguez-Abreu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Hoffmann-La Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer-Ingelheim. D.C. Cho: Advisory / Consultancy: Puretech; Advisory / Consultancy: Nektar Therapeutics; Advisory / Consultancy: HUYA; Advisory / Consultancy: Prometheus; Advisory / Consultancy: Genentech; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Exelixis. M.J. Riese: Advisory / Consultancy: Abbvie; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self): Incyte. A. Gupta: Leadership role, Employed by Nektar: Nektar Therapeutics. T. Chan: Leadership role, Employed by Nektar: Nektar Therapeutics. R. Saab: Leadership role, Employed by Nektar: Nektar Therapeutics. S. Singel: Leadership role, Employed by Nektar: Nektar Therapeutics. W. Lin: Leadership role, Employed by Nektar: Nektar Therapeutics. M. Tagliaferri: Advisory / Consultancy, Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Employed by Nektar: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Bluebird Bio. D.R. Spigel: Honoraria (institution), Research grant / Funding (institution): Abbvie; Honoraria (institution), Research grant / Funding (institution): Aeglea; Honoraria (institution), Research grant / Funding (institution): Amgen; Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Research grant / Funding (institution): Celgene; Honoraria (institution): Evelo; Honoraria (institution), Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Research grant / Funding (institution): Genentech/Roche; Honoraria (self), Research grant / Funding (institution): GlaxoSmithKline; Honoraria (institution): Illumina; Honoraria (institution), Research grant / Funding (institution): Ipsen; Honoraria (institution), Research grant / Funding (institution): Lilly; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Moderna Therapeutics; Honoraria (institution), Research grant / Funding (institution): Nektar; Honoraria (institution), Research grant / Funding (institution): Novartis; Honoraria (institution): PharmaMar; Honoraria (institution), Research grant / Funding (institution): Pfizer; Honoraria (institution), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Transgene; Honoraria (institution): Armo; Honoraria (institution): Precision Oncology; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): CellDex; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Grail; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): OncoGenex. All other authors have declared no conflicts of interest.

Background JZCA is a phase Ia/Ib study with the primary objective to assess the safety and tolerability of LY3381916 as monotherapy (Part A) and in combination with LY3300054, an anti-PD-L1 antibody (Part B). In the doseescalation part, safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of LY3381916 monotherapy (Part A) and in combination with LY3300054 (Part B) were investigated in patients (pts) with advanced solid tumors to determine the recommended phase II dose (RP2D). Methods Pts with advanced/metastatic solid tumors received LY3381916 orally from 60mg-600mg once daily (QD), 240mg twice daily (BID) (Part A), or LY3381916 60mg-240mg QD in combination with LY3300054 700mg intravenously every 2 weeks (Part B). Results LY3381916 was administered to 42 pts at the cut-off date of July 12, 2019. The most common treatmentrelated adverse events (AEs) were nausea and fatigue. Dose-limiting toxicities were observed in 3 pts (1 pt, Part A 240mg BID with Grade 3 [Gr] ALT/AST increase and systemic inflammatory response syndrome; 2 pts, Part B 240mg QD with Gr 3 fatigue and Gr 3 immunerelated hepatitis). The best objective response was SD, with 7 pts in monotherapy and 5 pts in combination dose escalation. LY3381916 clearance was 12 L/h; mean terminal half-life was ∼6h. Increases in drug exposure were proportional to dose with no apparent differences in PK between monotherapy and combination therapy. In monotherapy pts, PD data showed >90% IDO1 inhibition in ex-vivo whole blood and sustained reduction of plasma kynurenine (Kyn) at steady state for all doses. Sustained plasma Kyn reduction was observed in 76% of combination pts. Tumor tissue Kyn levels were decreased in > 60% of pts with treatment (67% mono; 64% combo). An increase in tumor CD8+ T cells (IHC and RNA-seq) was predominantly observed at the 240mg QD dose with LY3300054. RNA-seq expression was consistent with a dose-dependent increase in activated CD8 effector T cells (i.e., granzyme B, perforin) in the combination treatment. Conclusion LY3381916 is safely administered as monotherapy and in combination with LY3300054. The 240mg dose QD is the RP2D for combination with PD-L1 in expansion cohorts. Clinical trial identification NCT03343613. Editorial acknowledgement Editorial assistance was provided by Gina Moore, Syneos Health. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure B. O'Neil: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. S. Jalal: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Astex. C. Massard: Honoraria (institution): Eli Lilly and Company. J. Wallin: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. A. Szpurka: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company; Spouse / Financial dependant: Eli Lilly and Company. D. Wang: Full / Part-time employment: Eli Lilly and Company. V. Regnier Galvao: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. M.S. Xia: Full / Part-time employment: Eli Lilly and Company. K. Crowe: Full / Part-time employment: Eli Lilly and Company. S. Geeganage: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. T. Doman: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company; Spouse / Financial dependant: DWA Health Care Communications Group. L. Gandhi: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. X. Xu: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. J. Bendell: Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Five Prime; Research grant / Funding (institution): Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Medimmune; Advisory / Consultancy: Celgene; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Talhho; Advisory / Consultancy: Marcogenics; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): LEAP therapeutics; Research grant / Funding (institution): TG therapeutics; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: BI; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.

Background Despite a primary benefit, almost all patients (pts) develop acquired resistance to EGFR TKIs. Some mechanisms were related to the selective pressure of the different generations (G) EGFR TKIs, but the complete alteration profile at resistance remains to be elucidated. Methods Metastatic NSCLC pts who performed a tissue and plasma biopsy at EGFR TKI progression, and optionally before, were identified from the prospective MATCH-R trial (NCT02517892). Targeted next-generation sequencing (NGS, 74 to 82 genes), comparative genomic hybridization (CGH), whole-exome sequencing (WES), and RNA sequencing (RNA-Seq) were performed on the tissue. All molecular oncogenic alterations were classified as definitive/potential resistance mechanism or concomitant genetic alterations using OncoKB and Cancer Genome Interpreter. Results Among 62 pts included, tissue analysis at TKI progression was successful with NGS (94%), CGH (76%) and WES+RNA-Seq (53%). In the post 1st-2nd G EGFR TKI cohort (31 pts) the most frequent resistance alteration was p.T790M (n = 23, 74%). EGFR amplification (amp) was found in 7 (23%) pts and off-target mutations (mut) at resistance in 9 (29%, 2 KRAS, 2 JAK2, 1 PIK3CA, and 1 MET). Median PFS to EGFR TKI was 17 months (mo) for the pts with p.T790M as the only resistance mechanism vs 8 mo for the other resistance profiles (HR 2.42 [95% CI, 1.04-5.65]; p = 0.028). In the post 3rd G cohort (31 pts), acquired resistance alterations were mostly on-target (n = 12, 39%): 9 p.C797S, 2 p.L718Q and 1 EGFR amp. Off-target resistance alterations were found in 11 (35%) tumors: 5 fusions involving oncogenes (16%, RET, BRAF, ALK, and FGFR3), 2 BRAF p.V600E (6%), then MET amp, HER2 amp, KRAS mut, and PIK3CA mut in 1 pts (3%). p.T790M loss (54%) was associated with a shorter time to osimertinib discontinuation vs maintained (median 13 vs 22 mo; HR 2.16 (95% CI, 1.00-4.73); p = 0.046). More than one resistance mechanism was found in 12 (39%) and 14 (45%) pts in the post 1st-2nd and 3rd G cohort, respectively. Conclusions Genetic alteration landscape at EGFR TKIs progression is complex and heterogeneous since more than one resistance alteration was recognized in 42% of pts. Combination strategy might be needed. Legal entity responsible for the study Gustave Roussy, Cancer Campus. Funding Gustave Roussy, Cancer Campus. Disclosure Y. Loriot: Honoraria (self): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Pfizer; Honoraria (institution): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Incyte, Pfizer; Research grant / Funding (institution): Roche, MSD, Sanofi; Travel / Accommodation / Expenses: Roche, MSD, Janssen, AstraZeneca, Seattle Genetics; Licensing / Royalties: Pending patent (USA 62/455211, Europe 17209098.7). D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck, Novartis, prIME Oncology, Pfizer. S. Michiels: Advisory / Consultancy, Punctual statistical advice : IDDI Belgium, Janssen Cilag France; Advisory / Consultancy, Data and Safety Monitoring Member: Hexal, JJ Principal/sub-Investigator of Clinical Trials for AbbVie, Agios Pharmaceuticals, Amgen, Argen-X; Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. J-C. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: AstraZeneca and Gritstone. F. Andre: Research grant / Funding (institution): NVS, AZ, Roche, Daiichi, Lilly, Pfizer. G. Vassal: Advisory / Consultancy, Non-remunerated activity/ies: AstraZeneca, Bayer, BMS, Celgene, Incyte, Ipsen, Lilly, MSD, Merck, Pierre-Fabre, Novartis, Pfizer, Roche/Genentech, Servier, Takeda. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. All other authors have declared no conflicts of interest.

Background Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive cancer with low survival rates. Anti-PD-(L)1 antibodies are current treatment options for patients who progressed during or after platinum-based chemotherapy. While some of these patients achieve durable responses with anti-PD-(L)1 therapy, response rates are ≤21%; as such, novel therapies are needed for patients after treatment with platinum and anti-PD-(L)1 therapies. Enfortumab vedotin (EV) is an investigational humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is highly expressed in la/mUC. In a multicohort phase 2 study of EV (EV-201; NCT03219333), which included sites in Japan and Korea, single-agent EV 1.25 mg/kg was generally well tolerated. In Cohort 1 of EV-201 (closed to enrollment), EV demonstrated a confirmed ORR of 44% and a median DoR of 7.6 months as assessed by independent central review in patients with la/mUC with prior platinum chemotherapy and antiPD(L)1. Trial design EV-301 (NCT03474107) is a global, multicenter, open-label, phase 3 trial being conducted in the USA, Europe, and Asia, including sites in Japan, Korea, and Taiwan. Adult patients with la/mUC and an ECOG score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with anti-PD-(L)1 are eligible; these patients are consistent with the population in Cohort 1 of EV-201. Approximately 550 patients will be randomized (1:1) to receive EV (1.25 mg/kg) by IV on Days 1, 8, and 15 of each 28-day cycle (Arm A), or investigator’s choice of IV docetaxel, paclitaxel, or vinflunine (where approved) on Day 1 of each 21day cycle (Arm B). Treatment with EV will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include PFS, DoR, ORR, and assessment of safety/tolerability and quality-of-life parameters. Clinical trial identification NCT03474107. Legal entity responsible for the study Astellas Pharma US, Inc. Funding Astellas Pharma US, Inc. Disclosure D.P. Petrylak: Research grant / Funding (institution): Astellas ; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Bellicum; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (institution): Johnson and Johnson; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Millineum; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche Laboratories; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Clovis; Shareholder / Stockholder / Stock options: Tyme; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Innocrin. J.E. Rosenberg: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: EMD Serono. J. Lee: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Korea; Advisory / Consultancy, Research grant / Funding (institution): Ipsen Korea; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy: Novartis Korea; Advisory / Consultancy: Astellas Korea; Advisory / Consultancy: BMS Korea. I. Duran: Advisory / Consultancy: Seattle Genetics. Y. Loriot: Advisory / Consultancy: Astellas; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. G. Sonpavde: Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Onyx-Amgen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Agensys; Advisory / Consultancy: Astellas; Speaker Bureau / Expert testimony: Clinical Care Options; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Uptodate; Advisory / Consultancy: Biotheranostics; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Janssen; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: NCCN. C. Wu: Full / Part-time employment: Astellas. E.M. Gartner: Full / Part-time employment: Seattle Genetics, Inc. A. Melhem-Bertrandt: Full / Part-time employment: Astellas. T. Powles: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Merck; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

Background Pembrolizumab, a PD-1 inhibitor combined with platinum-based Ctx is standard therapy for eligible pts without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based Ctx and PD-1 inhibitors. Activation of inflammation and elevated baseline c-reactive protein (CRP) levels are associated with a lower response to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that showed a significant reduction in the incidence of fatal and nonfatal lung cancer in myocardial infarction pts with increased CRP levels (CANTOS study). Trial design CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating the safety and efficacy of docetaxel ± canakinumab in pts with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open-label) to confirm recommended phase 3 regimen (RP3R) to be used in the randomized phase 3 part (part 2 – double-blind, placebo-controlled). Key inclusion criteria: adult pts pretreated with one prior platinum-based Ctx and one prior PD-(L)1 inhibitor therapy for locally advanced or metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ∼9 pts will be enrolled to have at least 6 evaluable pts and ∼226 pts will be randomized (1:1, stratified by the number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by the incidence of dose-limiting toxicity in the first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives: overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator (RECIST v1.1), safety, PK, immunogenicity of canakinumab, and patient-reported outcomes. Part 1 is completed and part 2 is ongoing after confirming canakinumab 300 mg Q3W as RP3R. Clinical trial identification ACZ885V2301/NCT03626545. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure D. Lim: Advisory / Consultancy: MSD, Novartis, Astra-Zeneca, Boerhinger-Ingelheim; Honoraria (self): MSD, Novartis, Boehringer-Ingelheim. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. H. Kaneda: Honoraria (self): Novartis; Advisory / Consultancy: Novartis. J-H. Kang: Honoraria (self): Roche, AZ, Merck ; Advisory / Consultancy: AZ, MSD, Takeda; Research grant / Funding (self): AZ, Yuhan, CKD, Astellas. S-W. Kim: Advisory / Consultancy: AstraZeneca; Research grant / Funding (self): AstraZeneca, Lilly, Boehringer Ingelheim. C-H. Chiu: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche. J.C-H. Yang: Honoraria (self): Novartis, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Roche/Genentech, personal fees from Chugai, personal fees from MSD, personal fees from Pfizer, personal fees from Novartis, personal fees from BMS, persona; Advisory / Consultancy: Novartis, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Bayer, personal fees from Roche/Genentech, personal fees from Astellas, personal fees from MSD, personal fees from Merck Serono, personal fees from Pfizer. W-C. Su: Travel / Accommodation / Expenses: BI, BMS. K. Obyrne: Advisory / Consultancy: Boehringer Ingelheim, Merck Sharpe and Dohme, Eli Lilly, AstraZeneca, Roche, Pfizer, Bristol-Myers Squibb, and Novartis. V. Papadimitrakopoulou: Advisory / Consultancy: Nektar Therapeutics, AstraZeneca, Arrys Therapeutics, Merck, LOXO Oncology, Araxes Pharma, F Hoffman-La Roche, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Novartis, Takeda, AbbVie, TRM Oncology, Tesaro, Exelixis, Gritsto; Honoraria (self): F Hoffman-La Roche; Research grant / Funding (self): Eli Lilly, Novartis, Merck, AstraZeneca, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte (to institution). M. Reck: Speaker Bureau / Expert testimony: AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Honoraria (self): AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Officer / Board of Directors: IASLC BOD, Member of Scientific Committee. I. Malet: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, Glaxo Smith Kine, Incyte, AstraZeneca. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. L. Paz-Ares Rodriguez: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene.

Background Osimertinib is a 3rd-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-mutated (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in NSCLC CNS metastases. In the phase III FLAURA study (NCT02296125), osimertinib resulted in significant progression-free survival (PFS) benefit (primary endpoint; datacut off [DCO] 12 June 2017) over comparator EGFR-TKI (HR 0.46, p Methods Eligible patients (pts): ≥18 years (Japan: ≥20), treatment-naive with Ex19del/L858R EGFRm advanced NSCLC; WHO performance status 0–1. Pts with stable CNS metastases not requiring steroids for ≥2 weeks were allowed. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or comparator EGFR-TKI (gefitinib 250 mg qd/erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover was allowed for pts in the comparator EGFR-TKI arm upon central confirmation of progression and T790M positivity. Primary endpoint: PFS by RECIST v1.1, per investigator. OS was a secondary endpoint. DCO 25 June 2019. Results Globally, 556 pts were randomised to osimertinib (n = 279) or comparator EGFR-TKI (n = 277). Per study protocol, 70 (25%) pts crossed over from comparator EGFR-TKI to osimertinib. Osimertinib significantly improved OS vs comparator EGFR-TKI. All causality AEs, per investigator: osimertinib, 98% (grade ≥3, 42%); comparator EGFR-TKI, 98% (grade ≥3, 47%). AEs leading to discontinuation: osimertinib, 15%; comparator EGFR-TKI, 18%. The safety profile appears consistent with previously reported data. Table . LBA5_PR Efficacy output Osimertinib n = 279 Comparator EGFR-TKI n = 277 OS hazard ratio 0.799 (0.641, 0.997); p = 0.0462 (95.05% confidence interval) Median OS, months 38.6 31.8 (95% confidence interval) (34.5, 41.8) (26.6, 36.0) Deaths, total pts (%) 155 (56) 166 (60) Median follow-up for OS in all pts, months 35.8 27.0 Median follow-up for OS in censored* pts, months 43.1 43.1 12-month survival rate, % 89 83 (95% confidence interval) (85, 92) (77, 87) 24-month survival rate, % 74 59 (95% confidence interval) (69, 79) (53, 65) 36-month survival rate, % 54 44 (95% confidence interval) (48, 60) (38, 50) OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O’Brien-Fleming approach was required due the previous interim analysis.*Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Conclusions Osimertinib provided a statistically significant and clinically meaningful improvement in OS vs comparator EGFR-TKI in first-line pts with EGFRm advanced NSCLC. Clinical trial identification NCT02296125. Editorial acknowledgement Natalie Griffiths, PhD, from iMed Comms, an Ashfield Company; funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Celgene, Takeda; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion, Kissei, Amgen, Janssen, ROXO. B.C. Cho: Honoraria (institution), Advisory / Consultancy: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc.. J. Vansteenkiste: Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Roche; Speaker Bureau / Expert testimony: AstraZeneca, BMS, MSD, Roche. C. Zhou: Honoraria (self): Roche, Eli Lilly, Boehringer Ingelheim, Merck, Hengrui and Qiru. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca. P. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Merck, Takeda, Novartis, Genomic Health, Pfizer. M. Tiseo: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. F. Imamura: Honoraria (self), Research grant / Funding (institution): AstraZeneca. R. Hodge: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Shareholder / Stockholder / Stock options: AstraZeneca, Gritstone; Full / Part-time employment: AstraZeneca. D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck,Novartis, prIME Oncology, Pfizer. All other authors have declared no conflicts of interest.

Background Patients with advanced cervical cancer comprise a high-risk, poor prognostic group. Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target for these patients, though incorporation of the anti-VEGF agent bevacizumab to platinum- and taxane-based chemotherapy (CT) is associated with a modest OS benefit vs CT alone (median OS, 16.8 vs 13.3 mo; hazard ratio, 0.77, 95% CI, 0.62-0.95; P = 0.007; Tewari et al. Lancet. 2017). On the basis of an ORR of 14.3% (95% CI, 7.4-24.1) among 77 pretreated women with PD-L1–positive tumors in the cervical cancer cohort of KEYNOTE-158 (Chung et al. J Clin Oncol. 2019), the PD-1 inhibitor pembrolizumab was granted accelerated approval by the US FDA for patients with PD-L1–positive (combined positive score [CPS] of > 1) cervical cancer who had progressed during or after first-line CT. KEYNOTE-826 (NCT03635567) is a phase 3, randomized, double-blind, multinational study designed to evaluate the efficacy and tolerability of CT with or without pembrolizumab and/or bevacizumab in the first-line setting. Trial design Eligible patients with recurrent, persistent, or metastatic cervical cancer not previously treated with CT in a recurrent or metastatic setting who are not amenable to curative treatment will be randomized 1:1 to CT + pembrolizumab 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification will be performed by metastasis status at diagnosis, planned bevacizumab use (yes/no), and tumor PD-L1 CPS ( Clinical trial identification NCT03635567. Legal entity responsible for the study Merck & Co., Inc. Funding Funding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure K. Fujiwara: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharpe & Dohme Corp.; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Advisory / Consultancy: Takeda; Honoraria (self): Bayer; Honoraria (self): Daiichi Sankyo; Honoraria (self): Janssen Oncology; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Lilly Japan; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Zeria Pharmaceutical; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Kaken Pharmaceutical; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Oncotherapeutics. R. Shapira-Frommer: Honoraria (self): MSD Oncology; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Vascular Biogenics; Advisory / Consultancy: Clovis Oncology. J. Alexandre: Honoraria (self): Roche/Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis ; Honoraria (self): Sanofi/Aventis; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. B. Monk: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Advaxis; Advisory / Consultancy: Agenus; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Conjupro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Gradalis; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Immunomedics; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen/JohnsonJ Advisory / Consultancy: Mateon (formally Oxigene); Advisory / Consultancy: Merck; Advisory / Consultancy: Myriad; Advisory / Consultancy: Perthera; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Precison Oncology. T. Fehm: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer. N. Colombo: Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): TESARO, Inc.; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Takeda; Advisory / Consultancy: TESARO, Inc.; Advisory / Consultancy: BioCad. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy: Merck Sharpe & Dohme Corp.; Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Research grant / Funding (self): Yakult Honsha; Research grant / Funding (self): Pfizer. J.J. Li: Travel / Accommodation / Expenses, Full / Part-time employment: Merck & Co., Inc.; Travel / Accommodation / Expenses, Spouse / Financial dependant: Celgene. K. Stein: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.; Shareholder / Stockholder / Stock options: Novartis. S.M. Keefe: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. K. Tewari: Honoraria (self): TESARO, Inc.; Honoraria (self): Clovis Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Speaker Bureau / Expert testimony: AstraZeneca ; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Morphotek; Research grant / Funding (institution): Regeneron. All other authors have declared no conflicts of interest.

Background Neuregulin-1 gene (NRG1) fusions function as oncogenic drivers across various solid tumors, most notably in invasive mucinous adenocarcinoma (IMA) of the lung, and represent a rational potential target for treatment. NRG1 is a growth factor, which binds to ErbB3 or ErbB4 inducing the formation of ErbB3 or 4-containing homo- or heterodimers and activating downstream ErbB-family signaling pathways. Therefore, the ErbB-family blocker afatinib may be a potential treatment option for patients with solid tumors harboring NRG1 fusions. Methods We report a case series of all known patients with NRG1 fusion-positive solid tumors who were treated with afatinib; afatinib therapy is ongoing for some patients. Results To date, 18 patients with NRG1 fusion-positive solid tumors have been treated with afatinib (Table). These include 12 cases of non-small cell lung cancer (NSCLC; 7 of which were reported as IMA), 5 cases of gastrointestinal (GI) cancer (primarily pancreatic ductal adenocarcinoma [PDAC]) and 1 case of ovarian cancer. Various NRG1 fusion partners were identified, most commonly CD74 in patients with NSCLC (n = 7; 58%) and ATP1B1 in patients with gastrointestinal cancer (n = 3; 60%). Best response with afatinib among patients with NSCLC was partial response (PR) lasting 24 months (10 months among those specifically with IMA of the lung). Patients with PDAC experienced PR of 3 and 5.5 months' duration, and one patient has an ongoing PR after 7 months. One patient with cholangiocarcinoma had a PR lasting 8 months; another patient with ovarian cancer had stable disease (SD) of unknown duration.Table63OTableTumor typeNRG1 fusion partnerBest response, physician assessedDuration of response, mosRefsNSCLCIMACD74PR101CD74PR6.52CD74PD*3CD74SD33SDC4PD3CD74PD3CD74PR-4ADCSLC3A2PR121SDC4PR125-PR246CD74PR14+4, 6SDC4SD46GIPDACATP1B1PR37ATP1B1PR5.58APPPR7+6, 8CholangiocarcinomaATP1B1PR85Colorectal (KRASm +ve)POMKSD49OvarianCLUSD-10*PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Conclusions Afatinib is a potential treatment option for some patients with solid tumors harboring NRG1 fusions. The efficacy and safety of afatinib will be evaluated in ongoing/planned prospective non-randomized clinical trials of targeted drugs in patients with advanced cancer with potentially actionable genomic variants (NCT02925234 and NCT02693535). Editorial acknowledgement Greg Plosker of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study The authors. Funding Boehringer Ingelheim. Disclosure Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo Smith Kline; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin. J. Cadranel: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: AZ; Advisory / Consultancy, Non-remunerated activity/ies: BI; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy, Non-remunerated activity/ies: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis. B.A. Weinberg: Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen; Travel / Accommodation / Expenses: Caris Life Sciences; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Duruisseaux: Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): AbbVie; Honoraria (self): Boerhinger ingelheim. S.V. Liu: Advisory / Consultancy: Apollomics; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Heron; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Inivata; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Taiho (DSMB); Advisory / Consultancy: Takeda/Ariad; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Esanex; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Molecular Partners; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Rain Therapeutics; Research grant / Funding (institution): Threshold. K. Tolba: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Foundation One. R.C. Doebele: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Trovagene; Advisory / Consultancy, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials : Ignyta; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials: Loxo; Research grant / Funding (self): Mirati; Licensing / Royalties, Licensing fees from patents or biological materials : Abbott Molecular; Licensing / Royalties, Licensing fees from patents or biological materials : GVKbio; Licensing / Royalties, Licensing fees from patents or biological materials: Chugai; Licensing / Royalties, Licensing fees from patents or biological materials : Genentech; Licensing / Royalties, Licensing fees from patents or biological materials: Foundation Medicine; Licensing / Royalties, Licensing fees from patents or biological materials: Black Diamond. R.F. Schlenk: Research grant / Funding (self): Boehringer Ingelheim. J.J. Laskin: Honoraria (self), Research grant / Funding (self): Roche Canada; Honoraria (self): BI Canada; Honoraria (self): AstraZeneca Canada; Research grant / Funding (self): Pfizer Canada. P.K. Cheema: Honoraria (self), Advisory / Consultancy: Astrazeneca; Honoraria (self), Advisory / Consultancy: BI; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck. M.R. Jones: Full / Part-time employment: Qiagen. L.A. Muscarella: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. Solca: Full / Part-time employment: Boehringer Ingelheim. D.J. Renouf: Honoraria (self): Celgene; Honoraria (self): Tahio; Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Servier. All other authors have declared no conflicts of interest.

Background Rucaparib has clinical activity in patients with recurrent ovarian cancer with or without homologous recombination deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity) and is hypothesised to provide clinical benefit following frontline treatment. ATHENA (NCT03522246) is evaluating rucaparib + nivolumab as maintenance treatment following frontline platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for this combination includes the following: tumours with deleterious BRCA mutations or HRD express tumour-specific neoantigens, which attract PD-L1–expressing, tumour-infiltrating lymphocytes; rucaparib + anti-PD-1/PD-L1 demonstrated activity in a syngeneic ovarian cancer model; and PARP inhibitor–induced DNA damage may create a more antigenic tumour microenvironment regardless of HRD status. Trial design Patients are required to have completed cytoreductive surgery and achieved an investigator-assessed response to frontline, platinum-based doublet chemotherapy without disease progression or rising CA-125 during frontline treatment. Patients are randomised 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg twice daily + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumour HRD status, posttreatment disease status, and timing of surgery. Investigator-assessed progression-free survival (RECIST v1.1; primary endpoint) will be compared among arms. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, duration of response, and safety. Enrolment is ongoing; patients (n≈1000) will be enrolled at > 270 sites worldwide. Clinical trial identification NCT03522246. Legal entity responsible for the study Clovis Oncology, Inc. Funding Clovis Oncology, Inc. Disclosure K. Fujiwara: Research grant / Funding (institution): Advanced Oncotherapy; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Chugai-Roche; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): ImmunoGen; Research grant / Funding (institution): Kaken-Seiyaku; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Shionogi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Zeria Pharmaceutical. J-W. Kim: Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Janssen ; Research grant / Funding (institution): Genexine; Research grant / Funding (institution): GlaxoSmithKline ; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech ; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Tesaro. D.S. Tan: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Karyopharm; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech ; Advisory / Consultancy: Genmab; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Tessa Therapeutics. N. Katsumata: Honoraria (institution): AbbVie. K. Harano: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda. S. Hume: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. E. Jones: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. S. Goble: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. L. Sullivan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. D. Shih: Shareholder / Stockholder / Stock options, Full / Part-time employment: Clovis Oncology. R.L. Coleman: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Esperance; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): OncoMed; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: Bayer; Advisory / Consultancy: GamaMabs; Advisory / Consultancy: Genmab; Advisory / Consultancy: Gradalis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Tesaro. I. McNeish: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro. B. Monk: Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis Oncology ; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Janssen/Johnson & Johnson; Speaker Bureau / Expert testimony: Myriad; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony: Tesaro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Vermillion; Advisory / Consultancy: Verastem; Advisory / Consultancy: Precision Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Perthera; Advisory / Consultancy: NuCana; Advisory / Consultancy: Merck; Advisory / Consultancy: Mateon (formally OXiGENE); Advisory / Consultancy: Insys; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Gradalis; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Cerulean; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bayer. R. Kristeleit: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro. All other authors have declared no conflicts of interest.